The brain is a rich source of adenylate cyclase and phosphodiesterase, and the turnover of cyclic AMP there is rapid. Increasing evidence indicates that cyclic AMP is critically involved in neuronal function. The hydrolysis of cyclic AMP to 5'-AMP by phosphodiesterase is the only known mechanism by which the action of cyclic AMP is terminated. Studies on phosphodiesterase thus assume significance. We will continue to characterize phosphodiesterase(s) and its activator. Future work will include (1) Purification and characterization of the activator-dependent and activator-independent forms of phosphodiesterase; (2) Physical and chemical characterization of the protein activator specific for phosphondiesterase; (3) Subcellular localization of the enzyme and activator in tissues using immunofluorescence techniques; (5) Elucidation of the mechanism of activation of phosphondiesterase by the activator and by trypsin; (6) Determining whether the diminished phosphodiesterase activity in autopsy samples of patients affected with Reye's syndrome is associated with a particular form of phosphodiesterase; and (7) Elucidation of the mechanism by which nicotinic acid lowers intracellular level of cyclic AMP.